Fluorinated quinolones, process for their preparation and pharmaceutical preparations containing same

ABSTRACT

Antibacterial compounds of the following formula ##STR1## where the variables are as in claim 1 and their pharmaceutically acceptable bases.

This application is a 371 of PCT/FR 93/00505, filed 25 May 1995.

A subject of the present invention is new quinolones and moreparticularly quinolones substituted by a piperidine ring.

More particularly a subject of the invention is new piperidinylquinolone 3-carboxylic acids endowed with useful antibacterialproperties.

Specifically a subject of the invention is new6-fluoro-7-piperidine-quinolone-3-carboxylic acids of general formula I:##STR2## in which R is hydrogen or fluorine

Z is an amino radical

R₁ represents hydrogen, an (optionally hydroxylated lower alkyl)radical, an acyl radical derived from an organic carboxylic acid, analkyl carbonic acid or an aryl sulphonic acid or an arylamino carbonylradical of form: ##STR3## in which Ar represents a mono- or bicyclicaromatic radical optionally substituted by one, two or threesubstituents chosen from lower alkyls, halogens and trifluoromethyl

T represents oxygen or sulphur

m is equal to 1

X represents hydrogen or fluorine

Y represents hydrogen or fluorine

and R₃ is chosen from the group constituted by an isopropyl radical, atertbutyl radical, a cyclopropyl radical, a (cyclopropyl) alkyl radical,a phenyl radical or a phenyl radical substituted by one, two or threesubstituents defined previously

R₂ represents an oxygen atom linked by a semi-polar bond and n is equalto 0 or 1.

Among the compounds of the invention five sub-groups are distinguished:

the amino derivatives of formula I_(A) : ##STR4## in which R₁ representshydrogen, a linear or branched lower alkyl radical optionallysubstituted by a hydroxyl or an acyl radical defined as above

R, R₂ and n are defined as previously

and R₃ is a cyclopropyl radical

the amino derivatives of formula I_(B) ##STR5## in which R₁ representshydrogen, a linear or branched lower alkyl radical optionallysubstituted by a hydroxyl or an acyl radical derived from a carboxylic,carbonic or arylsulphonic acid

R₃ is a tertbutyl radical

and the substituents R, R₂ and n are defined as previously

the amino derivatives of formula I_(C) ##STR6## in which R₃ representsan isopropyl radical

and the substituents R, R₁, R₂ and n have the meanings providedpreviously

the amino derivatives of formula I_(D) ##STR7## in which R₃ represents aphenyl radical optionally substituted by one, two or three substituents

and the substituents R₁, R₂, R and n have the meanings providedpreviously

and the amino derivatives of formula I_(E) ##STR8## in which R₃represents a (cyclopropyl) alkyl radical in which the alkyl remainder ahas 1 to 3 carbon atoms

and the substituents R₁, R₂, R and n have the meanings providedpreviously.

Among the compounds of general formula (I), the compounds in which ZR₁is an ureido function are those which are currently preferred.

Particular emphasis is also given to the ureidic compounds of formulaI_(F) : ##STR9## in which R and R₃ have the meanings provided previously

T represents oxygen or sulphur

W is a group ≧C--H or ≧N

B is hydrogen or an aromatic structure with 5 or 6 members

V is hydrogen, a lower alkyl radical, a trifluoromethyl radical or ahalogen

and p is equal to 1, 2 or 3.

Among the compounds of general formula I, the compounds in which ZR₁ isan ureido function are those which are currently preferred.

The compounds according to the invention can be salified by the additionof a mineral or organic base. The main salts which can be used are thoseof alkali metals, alkaline-earth metals, ammonium, iron, aluminium,alkylamine salts, hydroxylalkylamine salts, phenylalkylamine salts,pyridylalkylamine salts, cyclanylamine salts, dicyclanylalkylamine salts. . .

Among the salts, sodium, lithium, ammonium, N-methylglucamine andtromethanol salts are those which are currently preferred.

These compounds can also be salified by a strong mineral or organic acidwhen R₁ represents hydrogen, a lower alkyl radical or a lower(hydroxyalkyl) radical. Among these, the hydrochlorides,methanesulphonates, lactates or acetates are preferred examples.

Among the compounds of general formula I, there can be mentioned quiteparticularly:

6,8-difluoro1-cyclopropyl-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid and its addition salts with a mineral or organic acid

6-fluoro-1-cyclopropyl-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid and its addition salts with a mineral or organic acid.

The compounds according to the invention possess remarkableantibacterial properties, in particular against Gram positive bacteria.

Moreover, they possess the property of being moderately resorbed bygeneral route in such a way that their elimination is essentiallyfaecal.

Therefore they can be used effectively as medicaments for bacterialinfections of the alimentary canal, for the treatment of bacterialdysenteries, of traveller's diarrhoea or of intestinal infections. Theycan also be used by topical route for the treatment of ocular infectionsor infections of the acoustic duct.

To this end, the compounds according to the invention will be used inthe form of pharmaceutical compositions in which the active ingredientof general formula I or one of its salts, is added to or mixed with apharmaceutically acceptable, non-toxic, inert excipient or vehicle.

The most appropriate pharmaceutical forms are those intended foradministration by digestive route such as solutes or drinkablesuspensions, granules, capsules, uncoated or coated tablets,sugar-coated pills, sachets of powder, flavoured or not, sweetened ornot, pills or cachets.

Solutions, creams, lotions, salts for topical application can also beused as an external antibacterial agent.

The average dose depends principally on the severity of the infectionand of the sensitivity of the microbial germ to the antibacterial agent.The unit dose ranges from 100 to 600 mg per dose. The daily dose rangesform 200 to 1200 mg spread over 2 to 4 doses.

The invention also relates to a process for obtaining the compounds ofgeneral formula I which consists of reacting a 6-fluoro-7-halogeno-1-R₃-4-oxo-1,4-dihydroquinoline-3-carboxylic acid of formula II: ##STR10##in which Hal represents an easily-exchangeable halogen atom and thesubstituents R and R₃ have the meanings provided previously with4-aminomethyl piperidine of formula III: ##STR11## in order to form a6-fluoro-1-R₃-7-((4-aminomethyl)-1-piperidinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid of formula IV: ##STR12## in which R₃ and R have the meaningsprovided previously which, if desired, can be

salified by the addition of a mineral or organic base

converted into the addition salt by the addition of a mineral or organicacid

N-oxidized by the action of a mineral or organic hydroperoxide

alkylated by the action of an alkyl halide in basic medium

or acylated by reacting with a functional derivative of carboxylic orsulphonic acid or also with an alkyl halogenoformate.

The invention also relates to a process for converting the aminocompound of formula IV into urea or thiourea which consists ofsubjecting the compound of formula IV to the action of an isocyanate orisothiocynanate of formula:

    Ar--N═C═T

in which

Ar and T have the definitions provided previously in solution in aninert solvent, in order to obtain the ureidic derivative of formula V:##STR13## in which R, R₃, T and Ar are defined as previously.

The following examples illustrate the invention without however limitingit.

EXAMPLE X

6,8-difluoro-7-[(4-aminomethyl)-1-piperdinyl]-1-(1-cyclopropyl)-4-oxo-1,4-dihydroquinolinyl-3-carboxylicacid (Compound 1)

A solution of 3 g (0.02M) of6,8-difluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and 3.6 g (0.03M) of 4-aminomethyl-piperidine in 30 ml of pyridineis heated under reflux for 5 hours.

At the end of this period of heating the crystals formed are taken up in50 cm³ of ethanol and the precipitate is separated out.

The precipitate is suspended in 50 cm³ of water for 30 minutes thenseparated, washed with water, washed with ethanol and dried. In this way2 g of crystals are collected melting (on a Koffler block) above 260° C.(the yield is 50% of the theoretical). The IR spectrum and themicroanalysis are in accordance with an anhydrous product. Thehydrochloride formed by taking up with 1N hydrochloric acid (30 cm³)also melts above 260° C. (yield 76%). The hydrochloride is in the formof pale yellow crystals which are moderately soluble in water.

The following were prepared in the same way:

6-fluoro-1-cyclopropyl-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid (compound 5)--(M.P.=236° C.) with a yield of 75%

The hydrochloride obtained with a yield of 55% melts above 260° C.

6,8-difluoro-1-(2,4-difluorophenyl)-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid--(M.p.>260° C.) with a yield of 48%

The hydrochloride obtained with a yield of 55% melts at 250° C.

6,8-difluoro-1-(cyclopropylmethyl)-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid--(M.p.=265° C.) with a yield of 72%

The hydrochloride obtained with a yield of 85% melts above 260° C.

6-fluoro-1-tertbutyl-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid--(M.p.>260° C.) with a yield of 24%

The hydrochloride obtained with a yield of 66% melts above 260° C.

6,8-difluoro-1-isopropyl-7-((4-aminomethyl)-1-piperidinyl)-quinolone-3-carboxylicacid (compound 7)--(M.p.=250° C.) with a yield of 88%

The hydrochloride obtained with a yield of 85% melts above 260° C.

The other 7-((4-aminomethyl)-piperidinyl)-quinolone-carboxylic acids areprepared by the action of 4-aminomethyl piperidine on the corresponding7-fluoro quinolone carboxylic acids.

They are isolated and tested in the form of hydrochloride or methanesulphonate.

EXAMPLE II

Bacteriological study of the compounds according to the invention

Material and Methods

The products were tested vis-a-vis 7 reference strains

* 4 gram positive genera:

Bacillus subtilis ATCC 9372

Straphylococcus aureus ATCC 25923

Streptococcus faecalis ATCC 8043

Staphylococcus aureus CB 951

* 3 gram negative genera:

Escherichia coli ATCC 25922

Pseudomonas aeruginosa ATCC 22853

Acinetobacter calcoaceticus variety anitratum ATCC 17903

Measurement of the minimal inhibitory concentrations was carried out bya microdilution technique (*) in liquid medium (Mueller-Hinton broth) ina volume of 100 μl and for a range of concentrations varying from 128 to0.6 mg/liter, prepared from a mother solution of antibiotic titrating512 mg/liter. The preparation of these mother solutions produced, variedaccording to the molecules as a function of solubility criteria.

The inoculation is carried out by adding to each cupule 10 μl of adilution in physiological water of an 18 hour broth of heart/brain brothsuch that each cupule contains about 10⁶ bacteria/ml.

The minimal inhibitory concentration is read as the first concentrationof antibiotic giving no culture which is macroscopically visible afterincubation for 18 hours at 37° C.

EXAMPLE III

Tablets of7-((4-aminomethyl)-1-piperidinyl)-6,8-difluoro-1-ethyl-4-oxo-1,4-dihydroquinolinyl-3-carboxylicacid hydrochloride at 250 mg

    ______________________________________                                        7-((4-aminomethyl)-1-piperidinyl)-6,8-difluoro-                                                          250    g                                           1-cyclopropyl-4-oxo-1,4-dihydroquinolinyl-                                    3-carboxylic acid hydrochloride                                               Maize starch               40     g                                           Wheat starch               40     g                                           Carboxymethyl starch       20     g                                           Polyvidone excipient       10     g                                           Microcrystalline cellulose 30     g                                           Magnesium stearate         10     g                                           ______________________________________                                    

for 1,000 finished tablets with an average weight of 0.400 g.

EXAMPLE IV

Opthalmic drops based on7-((4-aminomethyl)-1-piperidinyl)-6,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinolinyl-3-carboxylicacid lactate

    ______________________________________                                        7-((4-aminomethyl)-1-piperidinyl)-6,8-difluoro                                                           3      g                                           1-cyclopropyl-4-oxo-1,4-dihydroquinolinyl-                                    3-carboxylic acid lactate                                                     Disodium tetracemate       0.1    g                                           Disodium phosphate         0.05   g                                           Monosodium phosphate       0.04   g                                           Sodium hypophosphite       0.02   g                                           Methylparaben              0.015  g                                           Distilled water s.q.f.     100    ml                                          ______________________________________                                    

One drop contains 0.005 g of active ingredient.

                                      TABLE                                       __________________________________________________________________________    MINIMAL INHIBITORY CONCENTRATION (MIC) AND MINIMAL BACTERICIDAL               CONCENTRATION (MBC) (in μg/ml)                                                                                    Acinetobacter                                                                         S. aureus                      Bacterial                                                                            S. aureus                                                                             S. faecalis                                                                           E. coli P. aeruginosa                                                                         Baumanii                                                                              CB-951                         Genus  ATCC 25923                                                                            ATCC 25922                                                                            ATCC 25922                                                                            ATCC 22853                                                                            ATCC 17904                                                                            (1)                            Product                                                                              MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC                        __________________________________________________________________________    Compound 1                                                                           0.06                                                                              0.06                                                                              1   1   2   4   >16 >16 0.03                                                                              0.03                                                                              0.25                                                                              0.25                       Compound 2                                                                           0.015                                                                             0.015                                                                             0.25                                                                              0.5 2   2   >16 >16 0.003                                                                             0.007                                                                             0.03                                                                              0.06                       Compound 3                                                                           >51.2                                                                             >51.2                                                                             >51.2                                                                             >51.2                                                                             >51.2                                                                             >51.2                                                                             >51.2                                                                             >51.2       >51.2                                                                             >51.2                      Compound 4                                                                           0.06                                                                              0.12                                                                              0.12                                                                              0.12                                                                              0.06                                                                              0.06                                                                              1   1   0.12                                                                              0.12                                                                              2   2                          Compound 5                                                                           0.25                                                                              0.5         0.25                                                                              0.5                                                Compound 6                                                                           1.6 3.2 1.6 12.8                                                                              0.4 0.4 12.8                                                                              >51.2                                      Compound 7                                                                           3.2 6.4 3.2 25.6                                                                              1.6 1.6 25.6                                                                              >51.2                                      Cyproflox-                                                                           0.25                                                                              0.25                                                                              0.25                                                                              0.25                                                                              0.007                                                                             0.007                                                                             0.12                                                                              0.21                                                                              0.06                                                                              0.06                                                                              4   4                          acine                                                                         Pefloxacine                                                                          0.12                                                                              0.25                                                                              1   1   0.06                                                                              0.06                                                                              2   2   0.06                                                                              0.06                                                                              4   4                          __________________________________________________________________________     (1) Staphylococcus                                                            methicillino  resistant                                                       pefloxacino  resistant                                                   

I claim:
 1. A compound selected from the group consisting of a compoundof the formula ##STR14## wherein T is ═O or ═S, W is ##STR15## B ishydrogen or an aromatic of 5 to 6 ring members, V is selected from thegroup consisting of hydrogen, lower alkyl, --CF₃ and halogen, p is aninteger from 1 to 3, R is hydrogen or fluorine, R₃ is selected from thegroup consisting of cyclopropyl and phenyl optionally substituted with 1to 3 members of the group consisting of lower alkyl, --CF₃ and halogenor its salts with a non-toxic pharmaceutically acceptable base.
 2. Anantibacterial composition comprising a bactericidally effective amountof a compound of claim
 1. 3. A method of combatting bacterial infectionsin warm-blooded animals comprising administering to warm-blooded animalsa bactericidally effective amount of a compound of claim 1.